Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution

Zhang, Faming; Strand, Arne; Robbins, David J.; Cobb, Melanie H.; Goldsmith, Elizabeth J.

doi:10.1038/367704a0

Cited by 593 publications

(579 citation statements)

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“…The Arg∆ 528 Pro substitution also occurs within this kinase domain, resulting in a non-conservative amino acid change, replacing a positively charged residue with an apolar, uncharged one. X-ray crystallography of other serine/threonine kinases suggests that this highly conserved arginine and preceding conserved glutamate are essential for kinase function (Zhang et al, 1994). The Asn∆ 564 Tyr substitution occurs outside the kinase domain, but also results in a non-conservative amino acid replacement, exchanging a polar uncharged residue to an aromatic non-polar one.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Francis-Thickpenny

Richardson

et al. 2001

Br J Cancer

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Summary Epithelial ovarian carcinoma is often diagnosed at an advanced stage of disease and is the leading cause of death from gynaecological neoplasia. The genetic changes that occur during the development of this carcinoma are poorly understood. It has been proposed that IGFIIR, TGFβ1 and TGFβRII act as a functional unit in the TGFβ growth inhibitory pathway, and that somatic loss-of-function mutations in any one of these genes could lead to disruption of the pathway and subsequent loss of cell cycle control. We have examined these 3 genes in 25 epithelial ovarian carcinomas using single-stranded conformational polymorphism analysis and DNA sequence analysis. A total of 3 somatic missense mutations were found in the TGFβRII gene, but none in IGFRII or TGFβ1. An association was found between TGFβRII mutations and histology, with 2 out of 3 clear cell carcinomas having TGFβRII mutations. This data supports other evidence from mutational analysis of the PTEN and β-catenin genes that there are distinct developmental pathways responsible for the progression of different epithelial ovarian cancer histologic subtypes.

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Section: Discussionmentioning

confidence: 99%

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Francis-Thickpenny

Richardson

et al. 2001

Br J Cancer

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“…The structure is compared with that of ERK2, which we solved previously (27) to understand how the common mechanism of activation by dual phosphorylation and the common specificity for proline is integrated with the unique specificity of these kinases for their activating enzymes, substrates, and inhibitors.…”

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confidence: 99%

“…The statistics for the data and structure refinement are given in Tables 1 and 2. Starting phases for the p38 structure were taken from the molecular replacement solution found using the program AMORE (30) and the coordinates for the entirety of the low activity form of ERK2 (27). While the first maps showed buildable density in the C-terminal domain, initially density for the smaller Nterminal domain was broken.…”

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confidence: 99%

The structure of mitogen-activated protein kinase p38 at 2.1-Å resolution

Wang

Harkins

Ulevitch

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The structure of mitogen-activated protein (MAP) kinase p38 has been solved at 2.1-Å to an R factor of 21.0%, making p38 the second low activity MAP kinase solved to date. Although p38 is topologically similar to the MAP kinase ERK2, the phosphorylation Lip (a regulatory loop near the active site) adopts a different fold in p38. The peptide substrate binding site and the ATP binding site are also different from those of ERK2. The results explain why MAP kinases are specific for different activating enzymes, substrates, and inhibitors. A model presented for substrate and activator interactions has implications for the evolution of protein kinase cascades.

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“…It has been hypothesized that this JNK pathway exerts a proapoptotic effect in mature oocytes and early embryos. MAPKs are activated by the phosphorylation of neighboring threonine and tyrosine residues within a T-X-Y sequence motif located in the activation loop of the kinase domain (Anderson et al, 1990;Payne et al, 1991;Zhang et al, 1994). Both phosphorylations are accomplished by dual-specificity mitogen-activated protein (MAP) kinase kinases, known as MEKs, MAPKKs, or MKKs (Crews et al, 1992;Kosako et al, 1992;Wu et al, 1992).…”

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confidence: 99%

Activation of p42 Mitogen-activated Protein Kinase (MAPK), but not c-Jun NH₂-Terminal Kinase, Induces Phosphorylation and Stabilization of MAPK PhosphataseXCL100 inXenopusOocytes

Sohaskey

Ferrell

2002

MBoC

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Dual-specificity protein phosphatases are implicated in the direct down-regulation of mitogenactivated protein kinase (MAPK) activity in vivo. Accumulating evidence suggests that these phosphatases are components of negative feedback loops that restore MAPK activity to low levels after diverse physiological responses. Limited information exists, however, regarding their posttranscriptional regulation. We cloned two Xenopus homologs of the mammalian dual-specificity MAPK phosphatases MKP-1/CL100 and found that overexpression of XCL100 in G2-arrested oocytes delayed or prevented progesterone-induced meiotic maturation. Epitope-tagged XCL100 was phosphorylated on serine during G2 phase, and on serine and threonine in a p42 MAPKdependent manner during M phase. Threonine phosphorylation mapped to a single residue, threonine 168. Phosphorylation of XCL100 had no measurable effect on its ability to dephosphorylate p42 MAPK. Similarly, mutation of threonine 168 to either valine or glutamate did not significantly alter the binding affinity of a catalytically inactive XCL100 protein for active p42 MAPK in vivo. XCL100 was a labile protein in G2-arrested and progesterone-stimulated oocytes; surprisingly, its degradation rate was increased more than twofold after exposure to hyperosmolar sorbitol. In sorbitol-treated oocytes expressing a conditionally active ⌬Raf-DD:ER chimera, activation of the p42 MAPK cascade led to phosphorylation of XCL100 and a pronounced decrease in the rate of its degradation. Our results provide mechanistic insight into the regulation of a dual-specificity MAPK phosphatase during meiotic maturation and the adaptation to cellular stress. INTRODUCTIONMembers of the mitogen-activated protein kinase (MAPK) family play fundamental roles in the cellular response to diverse extracellular stimuli, including mitogens, cytokines, and environmental stresses (reviewed by Waskiewicz and Cooper, 1995;Ferrell, 1996;Lewis et al., 1998;Davis, 2000;Pearson et al., 2001). Activation of p42 MAPK and p44 MAPK in quiescent fibroblasts, for example, contributes to the induction of cyclin D expression and entry into the cell cycle (Pagès et al., 1993;Sun et al., 1994;Brondello et al., 1995;Cheng et al., 1998). Constitutive activation of MAPK cascades can cause cell transformation in fibroblasts (Cowley et al., 1994;Mansour et al., 1994) and, in a context-dependent and MAPK-specific manner, either promote or prevent apoptosis (Xia et al., 1995;Meier and Evan, 1998;Bonni et al., 1999). Thus, from a cellular perspective, precise regulation of MAPK activity can literally signify the difference between life and death.The meiotic maturation of Xenopus oocytes provides an elegant system for studying the biochemistry of p42 MAPK regulation. Activation of the p42 MAPK cascade is important at multiple points during maturation: for the initial activation of Cdc2 triggering the G2-M transition (Sagata et al., 1988;Kosako et al., 1994bKosako et al., , 1996Gotoh et al., 1995;Palmer et al., 1998); for Cdc2 reactivation and the suppressi...

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Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution

Cited by 593 publications

References 50 publications

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

The structure of mitogen-activated protein kinase p38 at 2.1-Å resolution

Activation of p42 Mitogen-activated Protein Kinase (MAPK), but not c-Jun NH₂-Terminal Kinase, Induces Phosphorylation and Stabilization of MAPK PhosphataseXCL100 inXenopusOocytes

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Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution

Cited by 593 publications

References 50 publications

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

Analysis of the TGF β functional pathway in epithelial ovarian carcinoma

The structure of mitogen-activated protein kinase p38 at 2.1-Å resolution

Activation of p42 Mitogen-activated Protein Kinase (MAPK), but not c-Jun NH2-Terminal Kinase, Induces Phosphorylation and Stabilization of MAPK PhosphataseXCL100 inXenopusOocytes

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Activation of p42 Mitogen-activated Protein Kinase (MAPK), but not c-Jun NH₂-Terminal Kinase, Induces Phosphorylation and Stabilization of MAPK PhosphataseXCL100 inXenopusOocytes